Published on September 30, 2015
1. Obesity context of type 2 diabetes and medication perspectives
2. Review Article Obesity context of type 2 diabetes and medication perspectives Abha Pandit a , Abhay Kumar Pandey b, * a Department of Medicine, Index Medical College Hospital and Research Centre, Indore, MP, India b Department of Physiology, All India Institute of Medical Sciences, Bhopal MP, India 1. Introduction Obesity epidemic is fast spreading associated with diabetes mellitus, arterial hypertension and cardiovascular diseases. Rapid evolution of unfavourable lifestyles, without the availability of consistently safe and effective medications, constitute a serious healthcare challenge. Medical attitude by and large is treating the complications rather than obesity, e.g. dyslipidaemia, hypertension, diabetes and cardiovascular disorders. Weight reduction is integral to prevention and control of diabetes. Reduction of 5–10% weight in the obese diabetics improves glycaemic blood pressure and cholesterol control.1 Many anti-diabetic medicines cause weight gain making weight control difﬁcult to achieve. Targeting of physiological pathways without inducing weight gain may be a proper therapeutic strategy. There is lack of adequate long-term data on beneﬁts and risks of currently used drugs. The potential medical gains from treatment of obesity are however, enormous. 2. Pathogenesis of type 2 diabetes Genetic predisposition makes people mount positive energy balance under exposure to certain environmental changes. a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) x x x – x x x a r t i c l e i n f o Article history: Received 22 April 2015 Accepted 12 August 2015 Available online xxx Keywords: Type 2 diabetes Obesity Obese diabetics Anti-obesity drugs a b s t r a c t Drug therapy of obesity has harsh antecedent that many earlier introduced drugs are withdrawn from market. The drugs in present use lack sufﬁcient long-term efﬁcacy and safety data. The difﬁculty of reversing changing dietary habits and decline in physical activity, however, offers major scope for anti-obesity therapeutics, implied in managing the epidemic chronic inﬂammatory maladies and cardiovascular sequel. Metabolic syndrome, pre-diabetes and type 2 diabetes mellitus, commonly associate with obesity. Weight reduc- tion is crucial to prevent and control type 2 diabetes. This emphasizes rational choice of therapeutic regimens that do not themselves cause weight gain, and better promote weight loss. Such an aspect is addressed brieﬂy focusing upon the available newer anti-obesity drug options, in particular. # 2015 Indraprastha Medical Corporation Ltd. Published by Elsevier B.V. All rights reserved. * Corresponding author at: Department of Physiology, All India Institute of Medical Sciences, Saket Nagar, Bhopal 462024, India. Tel.: +91 9981087687. E-mail address: email@example.com (A.K. Pandey). APME-316; No. of Pages 6 Please cite this article in press as: Pandit A, Pandey AK. Obesity context of type 2 diabetes and medication perspectives, Apollo Med. (2015), http://dx.doi.org/10.1016/j.apme.2015.08.001 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/apme http://dx.doi.org/10.1016/j.apme.2015.08.001 0976-0016/# 2015 Indraprastha Medical Corporation Ltd. Published by Elsevier B.V. All rights reserved.
3. Their adipose tissue then expands and starts secreting peptides that contribute to development of insulin resistance.2 Under insulin resistant state, plasma-free fatty acids rise in obese people due to enhanced lipolysis. Their intracellular uptake and oxidation also increase. This impairs insulin- mediated glucose disposal in muscles. Production of glucose and its release from the liver are also stimulated.3 Insulin resistant state precedes the occurrence of frank type 2 diabetes by few years. The pancreatic beta cells of genetically predisposed individuals fail to fully compensate insulin resis- tance, resulting in effective insulin deﬁciency. Proinﬂammatory cytokines as TNF-alpha secreted by macrophages in adipose tissue play signiﬁcant role in obesity-related insulin resistance. Type2 diabetesisthereforeastate bothofinsulin resistanceand insulin deﬁciency. Type 2 diabetics with obesity bears higher serum total cholesterol, LDL, VLDL and triglyceride and decreased HDL compared to non-obese T2DM.4 3. Therapeutic perspectives in type 2 diabetes Addressing lifestyle aspects, e.g. diet, exercise and weight loss, has great signiﬁcance in diabetes management. Intensive programmes addressing diet, physical activity and behavioural factors render valuable beneﬁts.5–7 Medical history should be obtained for assessing the multiple determinants of obesity, including dietary and physical activity patterns, psychosocial factors, weight-gaining medications and familial traits. Empha- sis on the complications of obesity to identify patients who will beneﬁt the most from treatment is more useful than using body mass index (BMI; calculated as weight in kilograms divided by height in metres squared) alone fortreatment decisions. Weight loss is achieved by creating a negative energy balance through modiﬁcation of food and physical activity behaviours. Treat- ment can be implemented either in a clinician's ofﬁce or by referral to a registered dietician or commercial weight loss programme. Weight loss of 5–10% is the usual goal. It is not necessary for patients to attain a BMI of less than 25 to achieve a health beneﬁt.8 The physical activity is judged adequate for daily 30-minute non-stop activity, at least ﬁve days in a week. High wellness standards have also been formulated as walking 10,000 steps a day, etc. Comparative study spanned over one and half year, reported in obese individuals of 22–72 year age range. Matched groups were assigned to take diet categories deﬁned as carbohydrate restriction, macronutrient balanced, calorie restriction and fat restriction. Although strict adherence was low, each deﬁned diet patterns yielded modest loss of body weight and reduction in associated cardiac risk job assessment at 1 year. More adhering individuals had superior beneﬁts.9 Cochrane review of weight reduction drug trials indicated superior results with drug therapy combined with diet and lifestyle modiﬁcation, yielding overall 3 kg or greater weight loss over 12- to 18-month therapies.10 Diet and lifestyle control over 4 years achieved 5% weight loss only in less than half of the people and after discontinuation of the intensive pro- gramme tendency to regain weight was manifest, particularly attributable to depression.11 Weight loss drugs are indicated for people with BMI more than 30 or above 27 with obesity associated comorbidity.12 Diabetes medications range from mono-therapy or combi- nation of oral anti-diabetic drugs to the insulin replacement regimens. The sulfonylurea drugs lower glycosylated haemo- globin (HbA1c) level by 1.5–2%. The nonsulfonylurea (repagli- nide, nateglinide etc.) is lesser in effect.13 These insulin secretagogue drugs cause around 2–3 kg of weight gains.14 Thiozolidinediones, which enhance insulin sensitivity of tissues, take longer for similar decrease of HbA1c. They also cause weight gain of 1.5–4 kg.15,16 Insulin, the most efﬁcient anti-diabetic, increases weight by about 1.8 kg per 1% reduc- tion in HbA1c.17 4. Weight neutral or weight lowering anti- diabetic drugs The weight neutral category of anti-diabetic drugs includes DPP4 inhibitors, acarbose and miglitol. This aspect is consid- ered for making therapeutic choices. Metformin, a biguanide, reduces insulin resistance without weight gain. It is difﬁcult to use due to frequent adverse effects. Metformin is also used in preventing disease in pre-diabetics, obese and women with history of gestational diabetes.18 The drug enhances insulin responsiveness and decreases hepatic glucose production. HbA1c is reduced by 1.5–2%, also improving the lipid proﬁle. Metformin is contraindicated in renal impairment, congestive heart failure and in persons predisposed to developing metabolic acidosis. Other anti-diabetics causing weight loss include pramlintide, exenetide and liraglutide. 5. The incretin hormones Glucagon, such as peptide 1, affects blood glucose control through several mechanisms including enhancement of glucose dependant insulin secretion, slowing of gastric emptying, regulation of post-prandial glucagon and reduction of food intake. Incretin effect implies greater insulin stimulant effect of oral glucose, compared to intravenously given glucose. This illustrates gluco-homiostatic inﬂuence of GLP1.19 A likely deﬁciencyofGLP1 indiabetesdecreasestheincretineffect.GLP1 is secreted from intestinal L cells, in response to nutrients causing the glucose-dependant insulin release. The dipeptidyl peptidase 4 enzyme (DPP4) rapidly degrades GLP1, restricting it to very short half life.20 Analogues of GLP1, exenatide and liraglutide are available to treat type-2-diabetes as ﬁrst line drugs for the obese patients, in whom metformin cannot be used. These are injectables with available option of slow release formulationandavoidedinpatientswithhistoryofpancreatitis. Exenatide is avoided in renal dysfunction with creatinin clearance under 30 ml. DPP4 inhibitor drugs incretin system boosts up the role of DPP4 inhibitor drugs like sitagliptin, saxagliptin, linagliptin, alogliptin, etc. These inhibit degradation of endogenous GLP1 and GIP (glucose dependant insulin-otropic peptide). They reduce HbA1c level with very little risk of hypoglycemia or weight gain. DPP4 inhibitors are safe and effective treatment option for an obese diabetic. They synergise with metformin in combination regimen. Caution required as renal dysfunction and rarely serious allergic reactions can occur. Liraglutide, a a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) x x x – x x x2 APME-316; No. of Pages 6 Please cite this article in press as: Pandit A, Pandey AK. Obesity context of type 2 diabetes and medication perspectives, Apollo Med. (2015), http://dx.doi.org/10.1016/j.apme.2015.08.001
4. GLP.1 analogue antidiabetic, causes weight loss.21 Amylin is satiety inducing peptide co-secreted with insulin and is deﬁcient in the diabetics. Injectable amylin analogue pramlin- tide is indicated in diabetics on insulin treatment, exhibiting poorly controlled postprandial hyperglycaemia.22 Low efﬁcacy proﬁle of the drug limits its use in obese patients with mealtime insulin. SGLT2 (sodium glucose linked transporter 2) inhibitors are new class of novel anti-diabetic agents. In diabetic patients, overactive SGLT2 present in proximal convoluted tubule curtail glycosuria during hyperglycaemia. SGLT2 inhibitors thus selectively facilitate the excretion of excess glucose in the diabetics. The effect has no relation to insulin. The calorie loss is desirable in the obese diabetics. Treatment with SGLT2 inhibitors such as canagliﬂozin and dapagliﬂozin is shown to signiﬁcantly reduce waist circumference of obese patients.23 These agents however associate all adverse consequences of glycosuria. They may raise serum creatinin and LDL-choles- terol and can cause hyperkelemia in cases with renal impairment or those taking potassium sparing drugs. Alfa glucosidase inhibitors – these oral anti-diabetic drugs inhibit intestinal carbohydrate digestive enzymes. These are weight neutral and useful in control of postprandial hyperglycaemia. Their efﬁcacy is minimal as adjuncts to check weight gain in obese diabetics.24 They are administered just prior to meals. Other agents: Additional drugs showing some utility for glycaemic control without risk of causing weight gain include colesevelam, a bile acid sequestrating agent,25 and the anti- Parkinsonian drug bromocriptine.26 Their action mechanisms are not yet characterized. 6. Anti-obesity drugs Orlistat is the most used anti-obesity drug for long-term management, and it primarily inhibits gastric and pancreatic lipases preventing the absorption of dietary fat. Orlistat therapy with exercise yields synergic beneﬁt for weight reduction and prevention of diabetes, and its progression. Four-year-long prospective orlistat therapy study in 3305 obese people resulted in signiﬁcant weight loss (5.8 kg versus below 3 kg in placebo group), and net 37% reduction of diabetes acquiring risk.27 Orlistat therapy also improves control of diabetes, systolic blood pressure, LDL and total cholesterol levels.28 Orlistat administration at 120 mg thrice daily, studied over 2 years reduced fat absorption by 30% and reduced 3% bodyweight on average, along with improved glycaemic, blood pressure and lipid control in obese diabetics.29 A Korean study of 24 weeks treatment resulted in average 2.73 kg (3.5% body weight) loss, along with signiﬁcant improvements in lipid proﬁle, fasting insulin, waist circumference, blood pressure, fasting blood glucose and glycosylated haemoglobin.30 Possi- bility of induced deﬁciencies of fat soluble vitamins and interaction with oral drugs need watch. Orlistat is avoided in malabsorption and cholestasis. Newer congener cetilstat is better tolerated. Phentermine + Topiramate: Antiepileptic drug Topiramate (Top) causes weight loss in the obese. Combination dosage form of phentermine hydrochloride with topiramate extended release may be used in overweight individuals bearing at least one weight related comorbidity.31 Phentermine (PT) is option for short-term weight loss in obese adults who exercise and eat a reduced calorie diet. It acts via hypothalamic catecholamine release towards reducing appetite. Topiramate induced weight loss may relate to effect on sodium channels, enhanced GABA activated ClÀ channels and inhibition of carbonic anhydrase isozyme. The drug signiﬁcantly reduces incidence of type 2 diabetes in obese persons. Standard dose is PT 7.5 mg + Top 46 mg daily. Usually it is started with PT 3.75 + Top 23 mg daily. It may be increased to PT 15 + Top 92 if weight loss of 5% body weight is not obtained, at 3 month, and subsequently discontinued if fails. One thousand two hundred and seven- ty-six adult obese, type 2 diabetic patients received 56-week therapy with PT + Top combination. Minimum dose level 3.75PT + 23Top led to 5.1% loss while 15PT + 92Top yielded 10.9% loss in bodyweight, as against only 1.6% loss in placebo group.32 Another 2487 obese individuals with 2 related comorbidities (e.g. Hypertension, prediabetes, type 2 diabetes, dyslipidaemia or abdominal obesity) received in groups, PT7.5/ Top 46 or 15/92 or placebo for 56 weeks. The average losses in body weight were 7.8% for PT7.5/Top 46; 9.8 for PT15/Top 92 and 1.2% for placebo.33 The weight losses were maintained in another 52-week extension (till 108 weeks total) of the trial, with respective 54% and 67% reduced risk of diabetes development for lower and higher dose regimens.34 Risk of metabolic acidosis due to bicarbonate loss (due to inhibition of carbonic anhydrase enzyme) needs concurrent address. Lorcaserin, a selective serotonin 2C receptor agonist acts centrally via melanocortin receptor 4, to induce satiety. It was approved for 10 mg twice daily dosing schedule in 2012. Six hundred and four obese type 2 diabetes patients on metfor- min + sulfonylurea regimen, received 5 mg BD or 10 mg BD drug for one year and accrued over 3% reductions of body weight on average.35 Only half the placebo group individuals attained such a weight loss. Mean glycosylated Hb was greatly reduced, but incidence of hypoglycaemias were increased. The drug outcome is assessed in the 12th week and weight loss of 3–5% body weight sufﬁces to discontinue treatment. The drug also associates risk of causing serotonin syndrome. Naltrexone + Bupropion sustained release combined therapy was approved in late 2014 for obesity treatment. Bupropion reduces energy intake and increases expenditure. Naltrexone blocks the counter compensatory mechanisms that would hamper sustaining weight loss. Non-diabetic obese individua- ls received NT32/BP 360 mg daily treatment. There was more than 4% body weight reduction on average, after one year.36 In 505 obese diabetics evaluated over 56 weeks on similar regimen, the average body weight loss was 5% in contrast to 1.8% in placebo group.37 There was signiﬁcant higher reduc- tion in glycosylated Hb levels as well.38 In a large study, obese type-2 diabetics on oral antidiabetic therapy were beneﬁted by signiﬁcant loss of body weight and improved HbA1c proﬁle consequent to administration of naltrexon SR/bupropion SR regime.39 Liraglutide is an agonist of Glucagon-like Peptide.1 receptor (GLP.1) in incretin, the endogenous satiety inducer gut hormone. Thirteen-hour long half-life of liraglutide allows once daily dosing at 1.2 and 1.8 mg in diabetes. Fifty-two-week study in 746 type 2 diabetics, compared liraglutide (1.2 and 1.8 mg), with 8 mg of glimipiride. Liraglutide consistently a p o l l o m e d i c i n e x x x ( 2 0 1 5 ) x x x – x x x 3 APME-316; No. of Pages 6 Please cite this article in press as: Pandit A, Pandey AK. Obesity context of type 2 diabetes and medication perspectives, Apollo Med. (2015), http://dx.doi.org/10.1016/j.apme.2015.08.001
5. reduced body weight by 2–2.5 kg while glimipiride caused weight gain over 1 kg. Glycosylated Hb was reduced 0.84% and 1.14% by two dose liraglutide regimens.40 The recommended dose is now 3 mg daily. Obese non-diabetic 3731 persons received 3 mg daily liraglutide over 56 weeks. Average 8% body weight loss was seen in treatment group as opposed to 2.6% in placebo control. A third of cases lost more than 10% body weight. In 846 obese diabetics, liraglutide 3 mg and 1.8 mg or placebo treatment for 56 weeks gave respectively 6%, 5% and 2% reduction of body weight. Sixty-nine percent of patients receiving 3 mg liraglutide achieved under 7 HbA1c level.41 A selective cannabinoid.1 receptor antagonist rimonabant exhibits central suppression of appetite as well as beneﬁcial peripheral metabolic effects. It is very risky in patients with depressive tendancy or suicidal ideation.42 Newer congeners lacking neurotoxicity are under research, due to sound promise of the group. 7. Bariatric surgery The option is for T2DM cases with higher than 35 BMI or those with BMI above 27 but having obesity linked comorbidity, and difﬁcult control of diabetes.43 In non-diabetics, respective levels of BMI are 40 or 35 with comorbidity. Gastric restriction and/or gut diversion surgery in obese case series followed over 10 years demonstrated amelioration of insulin resistance, metabolic syndrome and other comorbidities. Mortality rates were also lower.44 Prospective study of 4047 obese persons in matched groups of conventional medical versus bariatric surgery treatment, over 11 years, revealed moderately greater reduction of overall mortality in surgery group. Myocardial infarction rate was reduced to half and cancer to 60% compared to medical treatment group. Weight losses at 10- year assessment were stabilized in bariatric surgery to around 80% of the maximum reductions obtained within 1–2 years following surgery.45 Bariatric surgery gives 25–33% body weight loss and frequently remissions in diabetes.46 Problems include dumping syndrome, hypoglycaemia, micronutrient dysmetabolism and cholelithiasis. 8. Epilogue Drug therapy targeting pathways affecting glucose homios- tasis, satiety and weight would suit management of both diabetes and obesity. If patients are unable to attain 5% loss in body weight, adjunct long-term anti-obesity therapy is indicated. Patients most likely to beneﬁt from anti-obesity drugs are those with higher than 27 BMI associated with comorbidities viz. hypertension, diabetes, dyslipidaemia, obstructive sleep apnoea, etc.47 Choice of medication involves consideration of individual patients for comorbidities, other drugs taken and health contexts that would increase beneﬁt/ harm proﬁle of therapy. Many medications used for diabetes, other chronic morbidities and depression cause gain in weight. A proposed dictate is ‘‘treat obesity ﬁrst then treat comorbidi- ty’’, as obesity is recognized as disease now. There is no ‘‘one size ﬁts all’’ approach possible. Complexity of pharmacother- apy is due to variables as age and ethnicity. Varied distribution of metabolically active adipose tissue in different communi- ties can affect efﬁcacy of drug classes, and also make drugs loose efﬁcacy. Drug combinations that target multiple com- plimentary pathways of energy and calorie control have potential to promote better weight loss in broader heteroge- neous population. Newer drug therapies aim at targeting multiple mechanisms preferably by single molecules (e.g. tesofensine) but more feasibly through combinations, viz. qnexa, contrav, empatic and pramlintide + metreleptin. Obe- sity is chronic disease, while no anti-obesity drug is permitted for long-term continuation. Advance formulation technologies are also to be employed towards widening safety margins of drug therapy. Bariatric surgery is an option available to few and carries its own risks. Minimum targeted 3% reduction of bodyweight in morbid obesity reduces level of triglycerides, risk of development of diabetes and proﬁle of blood glucose and HbA1c. Greater weight losses lower raised blood pressure, improve LDL and HDL cholesterol proﬁle and requirement of medications for diabetes, hypertension, dyslipidaemia, etc.48 The obesity pandemic along with metabolic comorbidities seems to be enormous, with increase of ageing population. It would constitute essential basic skill therefore, to steward manage- ment of obesity with diabetes using the right therapeutic choices, in patients.49,50 Conﬂicts of interest The authors have none to declare. r e f e r e n c e s 1. Wing RR, Lang W, Wadden TA, Safford M, Knowler W, Bertoni AG. 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Review Article Obesity context of type 2 diabetes and medication perspectives Abha Pandita, Abhay Kumar Pandeyb,* aDepartment of Medicine, Index Medical ...
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