Vascular complications are the main challenge in the management of T2DM. In patients with T2DM, hypertension and prevalent microalbuminuria are common clinical features that guide treating physicians in assessing risk of cardiovascular and renal outcomes. Clinical evidence has shown a clear transitional path from microalbuminuria to chronic kidney disease  and a continuous relationship between albuminuria of any degree and increased cardiovascular mortality [17, 18].
In the United Kingdom Prospective Diabetes Study, one quarter of patients developed microalbuminuria within 10 years of being diagnosed with T2DM . Manifestations of urinary albumin progressed from normoalbuminuria to microalbuminuria at an annual rate of 2.0%, from microalbuminuria to macroalbuminuria at 2.8% annually, and from macroalbuminuria to diabetic nephropathy at 2.3% annually. Among patients with microalbuminuria, the study found an annual cardiovascular mortality rate of 2.0% compared with 3.5% in those with macroalbuminuria.
International guidelines for the treatment of T2DM recommend reducing the risk or slowing the progression of kidney disease through optimization of glycemic control . A variety of pharmaceutical options for reduction of hyperglycemia are available, including metformin, sulfonylureas and incretin-based therapies (GLP-1 analogs and DPP-4 inhibitors). For patients with T2DM, however, renal impairment can be a limiting factor in the selection of appropriate antihyperglycemic therapies. Metformin and some sulfonylureas have contraindications or recommended dose adjustments related to renal impairment. Dose adjustment is also recommended for all DPP-4 inhibitors except linagliptin when used in patients with moderate to severe renal impairment [12, 20]. Linagliptin, due to its predominantly non-renal route of elimination, requires no dose adjustment.
In this post hoc analysis of 512 patients with T2DM at high renal and vascular risk (defined as prevalent hypertension and microalbuminuria with T2DM), linagliptin showed significant and clinically relevant reductions in HbA1c and FPG in comparison with placebo. These findings were comparable to the efficacy results found in the individual six phase III trials [7–9, 13–15].
Along with these efficacy results, this analysis showed that linagliptin was well tolerated. At baseline, patients in the two treatment groups had well-matched clinical characteristics and similar backgrounds of antihypertensive therapies, with approximately 85% of each group receiving at least one drug in that class and 13% of each group receiving combination antihypertensive therapy. The incidence of hypoglycemia was markedly greater in the linagliptin group only when linagliptin was administered with sulfonylurea, which is consistent with clinical findings for other DPP-4 inhibitors [8, 21, 22]. This tendency may be attributable to the proposed uncoupling effect that sulfonylureas have on the glucose-dependent effects of incretin therapies . The percentage of patients receiving linagliptin who experienced serious AEs or AEs related to study drug was similar to those receiving placebo. Gastrointestinal AEs and infections, which are of concern in the DPP-4 class, occurred in similar proportions of patients in the linagliptin and placebo groups. No deaths occurred in either group.
Research suggests that GLP-1 may have beneficial effects on dyslipidemia, and recent small studies with DPP-4 inhibitors have shown favorable effects [24, 25] or a neutral effect  on postprandial dyslipidemia in patients with T2DM. The present analysis showed a reduction in mean triglyceride levels with linagliptin at LVOT, which was numerically greater than that seen with placebo.
Linagliptin had a modest effect on blood pressure, comparable to studies with other DPP-4 inhibitors, which have shown small to neutral effects on blood pressure [24, 26–28]. Minor changes were also observed in UACR with linagliptin treatment. In a recent post-hoc analysis of pooled Phase III data, linagliptin significantly reduced UACR after 24 weeks compared with placebo . The change in mean UACR versus baseline was -32% (95% CI: -42, -21; P < 0.05) with linagliptin. Patients in this earlier analysis were defined as having albuminuria ranging from micro- (UACR, >30 to ≤300 mg/g) to macroalbuminuria (UACR >300 to ≤3000 mg/g) and were on stable ACE inhibitor/angiotensin II receptor blocker background therapy. Hence, differences in baseline UACR levels along with more frequent concomitant treatment with renin–angiotensin–aldosterone system inhibitors may have contributed to the larger reduction in UACR in that analysis. In order to specifically evaluate the albumin-lowering potential of linagliptin a randomized, controlled trial has recently been initiated (clinicaltrials.gov: NCT01792518, MARLINA). So far, however, research on the use of DPP-4 inhibitors in patients with renal dysfunction or albuminuria has been limited. The present analysis did not evaluate the efficacy or safety of linagliptin by subgroups of renal function, but baseline eGFR data were included to provide a full description of the clinical characteristics of the population with both microalbuminuria and hypertension. DPP-4 inhibitors have previously been shown to be efficacious and well tolerated at reduced doses in patients with moderate to severe renal impairment [30, 31]. In clinical trial populations that included patients with mild and moderate renal impairment, linagliptin has been shown to be an efficacious and well-tolerated treatment without dose adjustment [7, 9, 15]. A phase I clinical trial with linagliptin showed that renal impairment ranging from mild to end-stage renal disease had no clinically meaningful effects on its pharmacokinetics . Additionally, a recently published phase III trial of patients with severe renal impairment, demonstrated that treatment with linagliptin 5 mg daily provided clinically meaningful reductions in HbA1c over 1 year (-0.7%, 95% CI: -21.0 to -20.4; P < 0.0001) with similar tolerability to placebo .
In patients treated with linagliptin in the present analysis, incidence of severe hypoglycemia was very low, body weight and renal function remained stable, and no cases of drug-related renal failure were reported, suggesting that linagliptin can be used safely in all patients and even in this highly susceptible patient population with severe renal impairment.
The findings of this study are limited by the post hoc pooled nature of the analysis. Patients who participated in any of six randomized, placebo-controlled, phase III trials, had different background antidiabetic therapies. The analysis was also based on a relatively short duration of 24 weeks or less, which does not allow for long-term safety assessments. However, taken together with previous reports of up to 2 years in patients with T2DM [7–9, 13–15, 34], these results provide further evidence of beneficial glycemic effects and tolerability in this population. The ongoing CAROLINA trial (clinicaltrials.gov: NCT01243424) is investigating long-term cardiovascular outcomes with linagliptin. This trial will include patients with vascular-related end-organ damage (such as moderate renal dysfunction or microalbuminuria) as well as patients with prevalent cardiovascular risk factors, such as hypercholesterolemia or hypertension, and will allow for long-term safety assessments. It is the first long-term, clinical evaluation of a DPP-4 with an active comparator.
In conclusion, in patients with T2DM complicated by hypertension and microalbuminuria, linagliptin 5 mg once daily is well tolerated and improves glycemic control. Linagliptin may support long-term metabolic therapeutic strategies to treat patients at high risk of renal and cardiovascular disease.