Type II diabetes mellitus is a chronic metabolic disease characterized by insulin-resistance and insufficient pancreatic production of insulin, leading to increased blood glucose levels. This condition is a major risk factor for cardiovascular diseases and is the most common cause of end-stage renal disease (ESRD). There are 415 million patients around the world currently affected by it, and it is estimated that by the year 2020, they will reach 642 million.1 In Italy, 5.5% of the population is affected (5.3% men and 5.6% women), that is more than 3 million patients.2 Many strategies have been devised to manage this disease, in which, besides the necessary life style changes, pharmacologic treatment is paramount. Pharmacologic therapy is better than placebo in lowering the baseline blood glucose and glycated hemoglobin (Hb) levels; nonetheless, it is at least controversial whether this translates into a decreased global cardiovascular mortality. A recent meta-analysis outlined that the nine classes of glucose-lowering drugs [sulphonylureas, meglitinides, tiazolidinedions, inhibitors of α-glycosidase, inhibitors of sodium–glucose cotransporter 2 (SGLT-2), inhibitors of dipeptidyl peptidase 4 (DPP-4), glucagon-like peptide-1 (GLP-1) receptor agonists, basic and rapid insulin], alone or in combination, were not better than placebo (placebo or standard of care) in reducing cardiovascular mortality. The limitation of this analysis could be the low number of cardiovascular events in the studies, as well as the selection bias of the randomized clinical trials (RCTs) often enrolling high-compliance patients, and the short follow-up (median 6 months).3 At variance is the cardiovascular outcome of the EMPA-REG OUTCOME (Fig. 1) study, demonstrating a lower all-causes mortality for patients on Empagliflozin [hazard ratio 0.68, 95% confidence interval (CI) 0.57–0.82, P < 0.001], with a significant reduction of cardiovascular deaths (hazard ratio 0.62, 95% CI 0.49–0.77, P < 0.001) and hospitalizations for heart failure (hazard ratio 0.65, 95% CI 0.50–0.85, P = 0.002). These differences appeared early in the study and persisted throughout its duration. The study also highlighted a difference of −0.54 and −0.60% in Hb A1c (HbA1c) for the 10 or 25 mg/die groups, respectively, after 12 weeks, which progressively weaken to −0.24 and −0.36% at the 206th week. The authors reported that the glycemic targets were not reached by many patients, with mean glycated Hb of 7.81% in the treatment groups vs. 8.61% for the control after 206 weeks.4
Similar results were reported in the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) (Fig. 2): patients treated with Liraglutide 1.8 mg/die had fewer cardiovascular events (death, nonfatal myocardial infarction and nonfatal stroke) than placebo controls (hazard ratio 0.87, 95% CI 0.78–0.97, P < 0.001 noninferiority and P = 0.01 for superiority), with a particularly significant reduction in the risk of death (hazard ratio 0.78, 95% CI 0.66–0.93, P = 0.007). As far as the glycemic control, the authors reported a better control for the treatment patients with HbA1c values −0.4% lower than placebo. The pattern of cardiovascular benefits appears to differ from that in the EMPA-REG OUTCOME trial: in that setting, the benefits appeared much earlier than in the LEADER trial. According to the authors, the effect of Empagliflozin was secondary to hemodynamic changes, whether Liraglutide likely modified the progression of atherosclerotic vascular disease.5
Another important issue is the management of the drug therapy vis-à-vis the risk of hypoglycemia, which is associated with increased mortality. This problem is particularly relevant when considering patients older than 80 years. These patients are usually excluded from clinical trials, but the results of these studies are inappropriately applied to them. The main evidence in this situation is from four RCTs [(UKPDS) United Kingdom Prospective Diabetes Study, (ACCORD) Action to Control Cardiovascular Risk in Diabetes, (ADVANCE) Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation and (VADT) Veteran's Affairs Diabetes Trial], and some meta-analyses, recently reviewed by Lipska et al. According to the authors, intensive glycemic treatment increases the risk of hypoglycemia 1.3–3-fold compared with standard management; furthermore, the risk of severe hypoglycemia increases linearly with increasing age (hazard ratio 1.03 for each incremental year P < 0.001).6
Microvascular complications also deserve specific attention in diabetic patients. Almost 40% of diabetic patients (whether the disease has been diagnosed or not) have chronic kidney disease (CKD), and without appropriate monitoring and treatment could progress insidiously.
Some evidence suggests that intensive glycemic control could decrease the incidence and slow the progression of CKD in diabetic patients.7 In the ADVANCE study, the risk of ESRD, that is need for hemodialysis or kidney transplant, was 65% lower in the arm of the study on intensive glycemic control (HbA1c ≤ 6.5%), and these differences became evident after the second year of treatment.
Albuminuria also seems to improve with a more aggressive treatment: the risk of developing albuminuria decreases by 30% in patients with tighter glycemic targets, and the number of patients returned to normoalbuminuria increases as well.8 Similar results were reported in the UKPDS and Steno-2 studies.7 A potential kidney-protective effect has been suggested for glucose-lowering drugs acting on the incretin system (DPP-4 inhibitor and GLP-1 receptor agonist), manifested by decreased albuminuria (Table 1).7 In a retrospective analysis of four RCTs, Linagliptin 5 mg therapy, added to regular treatment with angiotensin-converting enzyme inhibitors or AT1 blockers (ARBs), was associated with a 28% reduction in albuminuria after 24 weeks (95% CI 0.53–0.98, P < 0.0357) over placebo, with the effect starting to appear during the first 12 weeks. The specific mechanisms leading to this effect are not yet completely understood, but could depend on the effect on body weight, arterial blood pressure and renal hemodynamics, or a direct effect on glomerular podocytes, or improvement in renal inflammatory responses.9
The EMPA-REG OUTCOME trial showed that in diabetic patients at high cardiovascular risk, Empagliflozin reduced clinical relevant renal events, in particular the new onset albuminuria (11.2 vs. 16.2%; hazard ratio, 0.62; P < 0.001), or worsening of nephropathy (0.61; 95% CI 0.53–0.70; P < 0.001); the need for dialysis was also less likely for the treated patients (0.3 vs. 0.6%, hazard ratio 0.45; P = 0.0409), even though the absolute numbers were low (13/4687 vs. 14/2333 for control).10
Diabetes mellitus is certainly a condition with intrinsic increased mortality. Accordingly, specific multilevel strategies have been devised to reduce the acute and chronic complications of the disease. Tighter glycemic targets seem to lead to better control of the progression of the kidney disease, but the supporting evidence is mainly based on indirect indicators, such as albuminuria.
The combination of these therapeutic solutions with well codified strategies (e.g. renin–angiotensin–aldosterone system blockers) could provide a significant prevention opportunity, able, in the near future, to radically change the natural history of cardiovascular and renal diseases in the diabetic patient. The treatment should be individualized to achieve a better glycemic control, aiming at limiting the risk of hypoglycemia, particularly in the elderly. Present day evidence could change our approach to diabetes mellitus: the paradigm has shifted from the mere glycemic control to a treatment with drugs not only affecting the metabolic aspect, but also able to decrease mortality, specifically cardiovascular mortality.
Conflicts of interest
There are no conflicts of interest.
1. International Diabetes Federation. IDF diabetes atlas. 7th ed.Brussels, Belgium: International Diabetes Federation; 2015.
2. ISTAT. Annuario Statistico Italiano 2014. Rome, Italy: ISTAT; 2014.
3. Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA
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