Patients with type 2 diabetes mellitus often require multifactorial pharmacological treatment due to different comorbidities. An increasing number of concomitantly taken medications elevate the risk of the patient experiencing adverse drug effects or drug interactions. Drug interactions can be divided into pharmacokinetic and pharmacodynamic interactions affecting cytochrome (CYP) enzymes, absorption properties, transporter activities and receptor affinities. Furthermore, nutrition, herbal supplements, patient’s age and gender are of clinical importance. Relevant drug interactions are predominantly related to sulfonylureas, thiazolidinediones and glinides. Although metformin has a very low interaction potential, caution is advised when drugs that impair renal function are used concomitantly. With the exception of saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors also show a low interaction potential, but all drugs affecting the drug transporter P-glycoprotein should be used with caution. Incretin mimetics and sodium–glucose cotransporter-2 (SGLT-2) inhibitors comprise a very low interaction potential and are therefore recommended as an ideal combination partner from the clinical–pharmacologic point of view.

Water drinking elicits profound pressor responses in patients with impaired baroreflex function and in sinoaortic-denervated mice. Healthy subjects show more subtle changes in heart rate and blood pressure with water drinking. The water-induced pressor response appears to be mediated through sympathetic nervous system activation at the spinal level. Indeed, water drinking raises resting energy expenditure in normal weight and obese subjects. The stimulus setting off the response is hypoosmolarity rather than water temperature or gastrointestinal stretch. Studies in mice suggest that this osmopressor response may involve transient receptor potential vanniloid 4 (Trpv4) receptors. However, the (nerve) cell population serving as peripheral osmosensors and the exact transduction mechanisms are still unknown. The osmopressor response can be exploited in the treatment of orthostatic and postprandial hypotension in patients with severe autonomic failure. Furthermore, the osmopressor response acutely improves orthostatic tolerance in healthy subjects and in patients with neurally mediated syncope. The phenomenon should be recognized as an important confounder in cardiovascular and metabolic studies.

There are many angles to consider in drug treatment of obese patients. On the one hand, some specific weight loss drugs are available, on the other, several drugs are associated with unintentional weight changes. When treating an obese patient for any given disease, several physiological changes may influence the pharmacokinetic properties of the drugs required. Thus, increased body weight may influence the efficacy and safety of some drug treatments. Even more complicated is the situation after weight reduction surgery. Due to the various changes to the gastrointestinal tract induced by the different surgical techniques used, and the dynamic changes in body composition thereafter, drug dosing has to be constantly reconsidered. Whereas all of these issues are of clinical importance, none of them have been investigated in the necessary depth and broadness to ensure safe and efficacious drug treatment of the massively obese patient. Individual considerations have to be based on comorbidities, concomitant medication, and on specific drug properties, for example, lipophilicity, volume of distribution, and metabolism. In this article we summarize the data available on different aspects of drug treatment in the obese patient with the hope of improving patient care.